Development of rationally designed vaccines is an important need that nanotechnology has tremendous potential to transform. Already nanoparticle developments are incorporated into approved small molecule therapeutics. Advances are making rapid progress toward ligand targeted nanoparticles exhibiting tissue selective delivery, which is precisely one of the key requirements for better vaccines. However, despite most antigens being highly hydrophilic, the vast majority of nanoparticle systems (NP) being developed for vaccines are best suited for efficient loading of hydrophobic payloads. An equally important problem is a lack of nanoparticle systems for vaccines that are biodegradable. We plan to generate and test a biodegradable NP vaccine platform to address both of these problems. We will investigate feasibility to incorporate hydrophilic antigens efficiently and to deliver them in concert with advanced adjuvants to Antigen Presenting Cells in a manner that can induce a protective immune response. This NP platform design is based on construction entirely with protein and peptide materials in a manner to permit versatile, tailored loading to accommodate most antigens, or combinations of antigens, as well as incorporation adjuvants to tailor the immune response, such as the highly charged CpG oligonucleotides. The NP design is entirely with simple peptides, helping to insure robust manufacturability and biodegradability. One of the structural materials will be adapted from a highly anionic portion of a bacteria protective capsule and used as a versatile anchor for hydrophilic antigens, while also acting as an antigen itself (and one for which an immune response is needed). Initially this platform will be tested for feasibility using a pair of antigens from Bacillus anthracis, which is an area of intense effort to develop a better vaccine. Therefore, successful feasibility also is expected allow development of a first product to fill a large need. Moreover, the same vaccine should be useful to vaccinate again other major Bacillus infection problems, such as multiple drug resistant staph. Also, the system should be easily adapted to carry other antigens and/or combinations of antigens. To determine feasibility of the proposed versatile NP vaccine system in this Phase I research plan, we first will construct the paired antigen constructs and assemble and characterize the colloidal properties of the NP system. We then will investigate its ability to generate immune responses to both antigens and provide protection from challenge with Anthrax toxin and, if successful, investigate protection from inhalation exposure to bacterial spores. With success, Phase II studies will be needed to address manufacturing, and preclinical pharmacology and toxicology to enable advancement to clinical investigation. PUBLIC HEALTH RELEVANCE: Development of rationally designed vaccines is an important need that nanotechnology has tremendous potential to transform, in particular with APC targeted nanoparticles that can carry multiple antigens and incorporate adjuvants that tailor the immune response. However, the vast majority of nanoparticle vaccine systems are hydrophobic and thus not ideal for most antigens since they are typically hydrophilic. An equally important problem is a lack of nanoparticle systems for vaccines that are biodegradable. The planned studies are to generate and test a biodegradable NP vaccine platform addressing both of these problems. This platform will be developed and tested for feasibility using a pair of antigens from Bacillus anthracis, which is an area of current need for a better vaccine and is expected to also have application for other major Bacillus infection problems, such as multiple drug resistant staph. With success, Phase II studies will be needed to address manufacturing, and preclinical pharmacology and toxicology to enable advancement to clinical investigation.